Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT8A68SW)

• DOT Name: Metalloproteinase inhibitor 4 (TIMP4)
• Synonyms: Tissue inhibitor of metalloproteinases 4; TIMP-4
• Gene Name: TIMP4
• Related Disease:
  Glioblastoma multiforme
  Prostate cancer
  Abdominal aortic aneurysm
  Adult glioblastoma
  Advanced cancer
  Alzheimer disease
  Astrocytoma
  Atrial fibrillation
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Cardiac disease
  Cardiac failure
  Cardiovascular disease
  Colorectal neoplasm
  Congestive heart failure
  Dementia
  Duchenne muscular dystrophy
  Endometriosis
  Hepatitis C virus infection
  Hepatocellular carcinoma
  Nephritis
  Obesity
  Osteoarthritis
  Periodontitis
  Polycystic ovarian syndrome
  Prostate carcinoma
  Psoriasis
  Renal cell carcinoma
  Systemic sclerosis
  Thyroid gland carcinoma
  Chronic obstructive pulmonary disease
  Myocardial infarction
  Type-1/2 diabetes
  Cataract
  OPTN-related open angle glaucoma
  Arthritis
  Childhood kidney Wilms tumor
  Coronary atherosclerosis
  Coronary heart disease
  Dilated cardiomyopathy
  Neoplasm
  Prostate neoplasm
  Stroke
  Thyroid cancer
  Thyroid tumor
  Wilms tumor
• UniProt ID: TIMP4_HUMAN
• Pfam ID: PF00965
• Sequence:
  MPGSPRPAPSWVLLLRLLALLRPPGLGEACSCAPAHPQQHICHSALVIRAKISSEKVVPA
  SADPADTEKMLRYEIKQIKMFKGFEKVKDVQYIYTPFDSSLCGVKLEANSQKQYLLTGQV
  LSDGKVFIHLCNYIEPWEDLSLVQRESLNHHYHLNCGCQITTCYTVPCTISAPNECLWTD
  WLLERKLYGYQAQHYVCMKHVDGTCSWYRGHLPLRKEFVDIVQP
• Function: Complexes with metalloproteinases (such as collagenases) and irreversibly inactivates them by binding to their catalytic zinc cofactor. Known to act on MMP-1, MMP-2, MMP-3, MMP-7 and MMP-9.
• Tissue Specificity: Abundant in heart and present at low levels in many other tissues.

Molecular Interaction Atlas (MIA) of This DOT

47 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Glioblastoma multiforme	DISK8246	Definitive	Altered Expression	[1]
Prostate cancer	DISF190Y	Definitive	Altered Expression	[2]
Abdominal aortic aneurysm	DISD06OF	Strong	Biomarker	[3]
Adult glioblastoma	DISVP4LU	Strong	Altered Expression	[1]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[2]
Alzheimer disease	DISF8S70	Strong	Biomarker	[4]
Astrocytoma	DISL3V18	Strong	Altered Expression	[5]
Atrial fibrillation	DIS15W6U	Strong	Altered Expression	[6]
Breast cancer	DIS7DPX1	Strong	Biomarker	[7]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[7]
Breast neoplasm	DISNGJLM	Strong	Altered Expression	[8]
Cardiac disease	DISVO1I5	Strong	Altered Expression	[9]
Cardiac failure	DISDC067	Strong	Altered Expression	[10]
Cardiovascular disease	DIS2IQDX	Strong	Altered Expression	[11]
Colorectal neoplasm	DISR1UCN	Strong	Altered Expression	[12]
Congestive heart failure	DIS32MEA	Strong	Altered Expression	[10]
Dementia	DISXL1WY	Strong	Altered Expression	[4]
Duchenne muscular dystrophy	DISRQ3NV	Strong	Biomarker	[13]
Endometriosis	DISX1AG8	Strong	Biomarker	[14]
Hepatitis C virus infection	DISQ0M8R	Strong	Altered Expression	[15]
Hepatocellular carcinoma	DIS0J828	Strong	Genetic Variation	[16]
Nephritis	DISQZQ70	Strong	Altered Expression	[17]
Obesity	DIS47Y1K	Strong	Altered Expression	[18]
Osteoarthritis	DIS05URM	Strong	Genetic Variation	[19]
Periodontitis	DISI9JOI	Strong	Altered Expression	[20]
Polycystic ovarian syndrome	DISZ2BNG	Strong	Biomarker	[21]
Prostate carcinoma	DISMJPLE	Strong	Altered Expression	[2]
Psoriasis	DIS59VMN	Strong	Biomarker	[22]
Renal cell carcinoma	DISQZ2X8	Strong	Altered Expression	[23]
Systemic sclerosis	DISF44L6	Strong	Altered Expression	[24]
Thyroid gland carcinoma	DISMNGZ0	Strong	Altered Expression	[8]
Chronic obstructive pulmonary disease	DISQCIRF	moderate	Biomarker	[25]
Myocardial infarction	DIS655KI	moderate	Genetic Variation	[11]
Type-1/2 diabetes	DISIUHAP	moderate	Genetic Variation	[11]
Cataract	DISUD7SL	Disputed	Biomarker	[26]
OPTN-related open angle glaucoma	DISDR98A	Disputed	Biomarker	[26]
Arthritis	DIST1YEL	Limited	Biomarker	[27]
Childhood kidney Wilms tumor	DIS0NMK3	Limited	Biomarker	[28]
Coronary atherosclerosis	DISKNDYU	Limited	Genetic Variation	[29]
Coronary heart disease	DIS5OIP1	Limited	Genetic Variation	[29]
Dilated cardiomyopathy	DISX608J	Limited	Biomarker	[30]
Neoplasm	DISZKGEW	Limited	Altered Expression	[31]
Prostate neoplasm	DISHDKGQ	Limited	Altered Expression	[32]
Stroke	DISX6UHX	Limited	Altered Expression	[33]
Thyroid cancer	DIS3VLDH	Limited	Altered Expression	[8]
Thyroid tumor	DISLVKMD	Limited	Altered Expression	[8]
Wilms tumor	DISB6T16	Limited	Biomarker	[28]

18 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Metalloproteinase inhibitor 4 (TIMP4).	[34]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Metalloproteinase inhibitor 4 (TIMP4).	[35]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Metalloproteinase inhibitor 4 (TIMP4).	[36]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Metalloproteinase inhibitor 4 (TIMP4).	[37]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Metalloproteinase inhibitor 4 (TIMP4).	[38]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Metalloproteinase inhibitor 4 (TIMP4).	[39]
Selenium	DM25CGV	Approved	Selenium decreases the expression of Metalloproteinase inhibitor 4 (TIMP4).	[40]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of Metalloproteinase inhibitor 4 (TIMP4).	[41]
Nicotine	DMWX5CO	Approved	Nicotine affects the expression of Metalloproteinase inhibitor 4 (TIMP4).	[42]
Isoproterenol	DMK7MEY	Approved	Isoproterenol decreases the expression of Metalloproteinase inhibitor 4 (TIMP4).	[43]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Metalloproteinase inhibitor 4 (TIMP4).	[44]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the expression of Metalloproteinase inhibitor 4 (TIMP4).	[45]
Scriptaid	DM9JZ21	Preclinical	Scriptaid affects the expression of Metalloproteinase inhibitor 4 (TIMP4).	[47]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Metalloproteinase inhibitor 4 (TIMP4).	[48]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the expression of Metalloproteinase inhibitor 4 (TIMP4).	[49]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane increases the expression of Metalloproteinase inhibitor 4 (TIMP4).	[50]
Nitrobenzanthrone	DMN6L70	Investigative	Nitrobenzanthrone affects the expression of Metalloproteinase inhibitor 4 (TIMP4).	[51]
PAF	DMRZAQW	Investigative	PAF increases the expression of Metalloproteinase inhibitor 4 (TIMP4).	[52]

1 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Metalloproteinase inhibitor 4 (TIMP4).	[46]

References

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• [8] Lysyl Oxidase (LOX) Transcriptionally Regulates SNAI2 Expression and TIMP4 Secretion in Human Cancers.Clin Cancer Res. 2016 Sep 1;22(17):4491-504. doi: 10.1158/1078-0432.CCR-15-2461. Epub 2016 Mar 30.
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• [16] TIMP-3 -1296 T>C and TIMP-4 -55 T>C gene polymorphisms play a role in the susceptibility of hepatocellular carcinoma among women.Tumour Biol. 2014 Sep;35(9):8999-9007. doi: 10.1007/s13277-014-2170-z. Epub 2014 Jun 7.
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• [20] Differential gene and protein expression of tissue inhibitors of metalloproteinases (TIMP)-3 and TIMP-4 in gingival tissues from drug induced gingival overgrowth.Arch Oral Biol. 2009 Jul;54(7):634-41. doi: 10.1016/j.archoralbio.2009.04.002. Epub 2009 May 17.
• [21] Differences in connective tissue gene expression between normally functioning, polycystic and post-menopausal ovaries.Mol Hum Reprod. 2004 Jan;10(1):7-14. doi: 10.1093/molehr/gah003.
• [22] Differences in Osteoimmunological Biomarkers Predictive of Psoriatic Arthritis among a Large Italian Cohort of Psoriatic Patients.Int J Mol Sci. 2019 Nov 10;20(22):5617. doi: 10.3390/ijms20225617.
• [23] mRNA expression of matrix metalloproteases and their inhibitors differs in subtypes of renal cell carcinomas.Eur J Cancer. 2001 Oct;37(15):1839-46. doi: 10.1016/s0959-8049(01)00215-5.
• [24] Circulating tissue inhibitor of matrix metalloproteinase-4 (TIMP-4) in systemic sclerosis patients with elevated pulmonary arterial pressure.Mediators Inflamm. 2008;2008:164134. doi: 10.1155/2008/164134. Epub 2009 Jan 25.
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• [26] TIMP1, TIMP2, and TIMP4 are increased in aqueous humor from primary open angle glaucoma patients.Mol Vis. 2015 Oct 13;21:1162-72. eCollection 2015.
• [27] Inhibition of adjuvant-induced arthritis by systemic tissue inhibitor of metalloproteinases 4 gene delivery.Arthritis Rheum. 2002 Dec;46(12):3361-8. doi: 10.1002/art.10648.
• [28] Inhibition of Wilms' tumor growth by intramuscular administration of tissue inhibitor of metalloproteinases-4 plasmid DNA.Oncogene. 2001 Jul 19;20(32):4337-43. doi: 10.1038/sj.onc.1204508.
• [29] MMP-2, MMP-9, and TIMP-4 and Response to Aspirin in Diabetic and Nondiabetic Patients with Stable Coronary Artery Disease: A Pilot Study.Biomed Res Int. 2017;2017:9352015. doi: 10.1155/2017/9352015. Epub 2017 Jul 10.
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• [31] Matrix metalloproteases and TIMPs as prognostic biomarkers in breast cancer patients treated with radiotherapy: A pilot study.J Cell Mol Med. 2020 Jan;24(1):139-148. doi: 10.1111/jcmm.14671. Epub 2019 Sep 30.
• [32] Monoclonal Antibody against CXCL1 (HL2401) as a Novel Agent in Suppressing IL6 Expression and Tumoral Growth.Theranostics. 2019 Jan 25;9(3):853-867. doi: 10.7150/thno.29553. eCollection 2019.
• [33] Small Vessel Disease Is Associated with Tissue Inhibitor of Matrix Metalloproteinase-4 After Ischaemic Stroke.Transl Stroke Res. 2019 Feb;10(1):44-51. doi: 10.1007/s12975-018-0627-x. Epub 2018 Apr 23.
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• [39] Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
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